Methods and kits for use in preventing restenosis

ABSTRACT

Kits and methods for their use are provided for at least inhibiting the progression of, if not preventing, restenosis in a host. In the subject methods, a vascular site is contacted, usually flushed, with a solution having a pH that is less than about 4, e.g. a hydrochloric acid. The subject kits methods find use in applications where the prevention of restenosis is desirable, including angioplasty applications, and may be used in combination with other treatment modalities, e.g. stents, and the like.

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application is a continuation-in-part of application Ser.No. 09/454,235 filed on Dec. 2, 1999 and issued as U.S. Pat. No.6,156,350 on Dec. 5, 2000; the disclosure of which is hereinincorporated by reference.

INTRODUCTION

[0002] 1. Technical Field

[0003] The field of this invention is vascular disease, particularlyrestenosis and the prevention or treatment thereof.

[0004] 2. Background of the Invention

[0005] “Restenosis” refers to the renewed narrowing of an artery, e.g. acoronary artery, following a vessel opening or widening procedure, suchas angioplasty or atherectomy. In restenosis, a vessel that has beentreated to at least minimize the volume of a lesion or blockage andthereby restore blood flow, e.g. by balloon angioplasty, starts torenarrow, typically within about six months of the vessel wideningprocedure. This renarrowing often requires additional treatment, such asadditional angioplasty procedures. It has been estimated that as much asone third to one half of all angioplasty procedures are followed byrestenosis within the first six months to one year following the initialvessel widening procedure.

[0006] The cause of restenosis, and therefore identification of ways toprevent it, is the subject of intense interest. While it is known thatrestenosis is not caused by blood clots forming at the widened site, thecause of restenosis is not completely understood. One theory holds thatrestenosis is the cause of smooth muscle overgrowth of the vessel wall,perhaps as a result of the presence of large amounts of oxidants.Another theory holds that smooth muscle growth is not the primary causeof restenosis. Instead, restenosis results from scarring, which resultsin a remodeling and narrowing of the vessel.

[0007] A number of different protocols have been developed and/or arecurrently being investigated to treat and/or prevent restenosis. Forexample, antioxidant drugs such as probucol (Lorelco™) have beenemployed with some success. Other smooth muscle cell proliferationinhibitors that have been tested for their ability to inhibit restenosisinclude calcium channel blockers, e.g. verapamil, and proteins such asangiopeptin. Another potential technique for preventing restenosis thatis currently being clinically evaluated involves the use of radiation,where the surface of the treated vessel is exposed to radiation, e.g.via the use of β-emitters. See e.g. the Beta-Cath™ System commercializedby Novoste Corporation and described at the website whose URL is made upby placing www. before “novoste” and “.com” after “novoste”. Yet othermethods involve the use of stents to mechanically maintain the openvessel.

[0008] While a variety of different protocols are currently being testedfor their effectiveness and safety in the prevention of restenosis (someof which have been described above), no particular technique has yetemerged as completely satisfactory. As such, there is continued interestin the development of new methods for preventing restenosis.

[0009] Relevant Literature

[0010] van der Wieken LR, “Stents and IIb/IIIa receptor blockerscombined: usefulness in various types of coronary artery disease,” SeminInterv Cardiol (1999 June) 4(2):77-83; Antoniucci et al., “Current roleof stenting in acute myocardial infarction,” Am Heart J (1999 August)138(2 Pt 2):147-52; Castella et al., “Prevention of CoronaryRestenosis,” Cardiol Rev (1999 July-August) 7(4):219-31; Marso et al.,“Intracoronary stenting: an overview for the clinician,” Cleve Clin JMed (1999 July-August) 66(7):434-42; Rees, “Stents for atheroscleroticrenovascular disease,” J Vasc Interv Radiol (1999 June) 10(6):689-705;Gunn et al., “Does stent design influence restenosis?” Eur Heart J (1999July) 20(14):1009-13; Yutani et al., “Coronary atherosclerosis andinterventions: pathological sequences and restenosis,” Pathol Int (1999April) 49(4):273-90; Johnson et al., “The utility of animal models inthe preclinical study of interventions to prevent human coronary arteryrestenosis: analysis and recommendations. On behalf of the Subcommitteeon Animal, Cellular and Molecular Models of Thrombosis and Haemostasisof the Scientific and Standardization Committee of the InternationalSociety on Thrombosis and Haemostasis,” Thromb Haemost (1999 May)81(5):835-43; Crocker, “Radiation therapy to prevent coronary arteryrestenosis,” Semin Radiat Oncol (1999 April) 9(2):134-43; Thaulow,“Pharmacologic effects of calcium channel blockers on restenosis,” JCardiovasc Pharmacol (1999) 33 Suppl 2:S12-6.

SUMMARY OF THE INVENTION

[0011] Methods and kits are provided for at least inhibiting theprogression of, if not preventing, restenosis in a host. In the subjectmethods, a vascular site is contacted, usually flushed, with a solutionhaving a subphysiologic pH, e.g. an acidic solution such as ahydrochloric acid solution. The subject methods find use in applicationswhere the prevention of restenosis is desirable and may be used incombination with other treatment modalities, e.g. stents,pharmacological restenosis inhibitors, and the like.

BRIEF DESCRIPTION OF THE FIGS.

[0012]FIGS. 1A and 1B show a normal untreated aorta at both 25× and 100×magnification.

[0013]FIGS. 2A and 2B show an aorta that was ballooned and treated witha control saline solution at 2 weeks.

[0014]FIGS. 3A and 3B show an aorta (at 25× and 100× magnification,respectively) that was ballooned and then treated with test solution A.

[0015]FIGS. 4A and 4B aorta (at 25 and 100× magnification, respectively)show the histology of an aorta that was ballooned and then treated withtest solution B.

[0016]FIGS. 5A and 5B show an aorta (at 25 and 100× magnification,respectively) that was ballooned and treated with a control salinesolution at 3 days.

DESCRIPTION OF THE SPECIFIC EMBODIMENTS

[0017] Methods are provided for use in the prevention of restenosis. Inthe subject methods, a vascular site of a host is contacted, e.g.flushed, with a solution having a subphysiologic pH, e.g. a solutionhaving a pH of less than about 4. The vascular site is contacted withthe solution of reduced pH for a period of time sufficient for at leastthe progression of restenosis at the vascular site to at least beslowed, if not prevented. The subject methods may be used in conjunctionwith other restenosis prevention protocols, e.g. stenting. Also providedare kits for use in practicing the subject methods. In furtherdescribing the subject invention, the subject methods are reviewed firstin greater detail, followed by a discussion of the subject kits andcomponents thereof for practicing the subject methods.

[0018] Before the subject invention is described further, it is to beunderstood that the invention is not limited to the particularembodiments of the invention described below, as variations of theparticular embodiments may be made and still fall within the scope ofthe appended claims. It is also to be understood that the terminologyemployed is for the purpose of describing particular embodiments, and isnot intended to be limiting. Instead, the scope of the present inventionwill be established by the appended claims.

[0019] It must be noted that as used in this specification and theappended claims, the singular forms “a,” “an” and “the” include pluralreference unless the context clearly dictates otherwise. Unless definedotherwise all technical and scientific terms used herein have the samemeaning as commonly understood to one of ordinary skill in the art towhich this invention belongs.

[0020] Methods

[0021] As summarized above, the subject invention provides methods forat least slowing the progression of, if not preventing the occurrenceof, restenosis at a vascular site of a host. In the subject methods, thetarget vascular site is contacted with a solution of subphysiologic pHfor a period of time sufficient for the progression of restenosis at thetarget site to at least be slowed.

[0022] The target vascular site that is contacted with the solution ofsubphysiologic pH during the subject methods is one that has beenpreviously treated for vascular occlusion, where the occlusion may be apartial or total occlusion. As such, the target vascular site is onethat has the potential for restenosis, i.e. renarrowing of the vesselwalls. The target vessel may be an artery or vein, and is usually anartery. The vascular site may be a peripheral or coronary vascular site,where the term peripheral is used broadly to refer to any site that isnot a coronary vascular site. As such, peripheral vascular sites includenot only limbic vascular sites but also core body vascular sites, e.g.carotid arteries, renal arteries, etc. In certain embodiments, thevascular site is a limbic peripheral vascular site, by which is meantthat the vessel in which the vascular site is located is a vessel foundin one of the extremities of the patient to be treated, i.e. the arms orlegs. Often, the vascular site is a site in a lower extremity vessel,e.g. a lower extremity artery. As indicated above, of particularinterest in certain embodiments are peripheral arterial vascular sites,where specific peripheral arteries of interest include: iliac arteries,femoropopliteal arteries, infrapopliteal arteries, femoral arteries,superficial femoral arteries, popliteal arteries, and the like. In yetother embodiments, the vascular site is present in a heart associatedvessel, e.g. the aorta, a coronary artery or branch vessel thereof, etc.In yet other embodiments, the vascular site is present in a carotidartery or a branch vessel thereof.

[0023] The vascular site is characterized by having been treated forvessel narrowing or occlusion prior to practice of the subject methods.The vessel may have been treated for a total or partial occlusion, wherethe nature of the occlusion may vary greatly. Thus, the vessel may havebeen subject to an angioplasty or atherectomy procedure, where theinitial vessel narrowing lesion has been manipulated in some fashion toenhance the blood flow rate through the vascular site. For example, thevascular site may be one that has been subjected to balloon angioplasty.Alternatively, the vascular site may be one that has been subjected tomechanical removal of at least a portion of the initially presentlesion, e.g. through use of a device such as the RotoblatorTm device. Inany event, the vascular site is one that is at least potentially subjectto vessel renarrowing or reconstriction. In other words, the targetvascular site is a site that has a propensity for vessel renarrowing,i.e. restenosis, to occur.

[0024] As mentioned above, the target vascular site is contacted with asolution of subphysiologic pH during practice of the subject methods. Asthe solution employed in the subject methods is a solution ofsubphysiologic pH, it is also properly referred to as an acidicsolution. A variety of different types of acidic solutions may beemployed in the subject methods. The acidic treatment solutions thatfind use in the subject methods generally have a pH of less than about6.5, where the pH is usually less than about 4.0 and more usually lessthan about 3.0. In many preferred embodiments, the pH ranges from 0 to2, and usually 0 to 1.

[0025] The acidic treatment solution can include a number of differenttypes of acids, where the acids may or may not include a hydrocarbonmoiety, i.e. a hydrogen bonded directly to a carbon atom. Suitable acidsthat lack a hydrocarbon moiety include halogen acids, oxy acids andmixtures thereof, where specific acids of interest of this type include,but are not limited to, hydrochloric, nitric, sulfuric, phosphoric,hydroboric, hydrobromic, carbonic and hydroiotic acids. For such acids,the acid can be a concentrated acid, or can be diluted. Upon dilution,the concentration of an inorganic acid will generally be from about 10 Nto about 0.01 N, preferably between 5 N to 0.1 N. Also of interest areacids that include a hydrocarbon moiety, where such acids include, butare not limited to, any organic acid of one to six (C₁ to C₆) carbons inlength. Organic acids of this type include, but are not limited to,formic, acetic, propionic, maleic, butanoic, valeric, hexanoic,phenolic, cyclopentanecarboxylic, benzoic, and the like. For an organicacid, the acid can be in concentrated form, or can be diluted. Theacidic treatment solution can be composed of either a monobasic or apolybasic acid. Acids are “monobasic” when they have only onereplaceable hydrogen atom and yield only one series of salts (e.g.,HCl). Acids are “polybasic” when they contain two or more hydrogen atomswhich may be neutralized by alkalies and replaced by organic radicals.

[0026] In many embodiments of the subject invention, the acid solutionis hypertonic, by which is meant that the osmolarity of the solution isgreater than that of whole blood, i.e. the osomolarity is greater than300 mosmol. The solution may be rendered hypertonic by including anyconvenient component or components in the solution which provide for thedesired elevated osmolarity.

[0027] Any convenient agent that is capable of increasing the osmolarityof the solution may be employed, where suitable agents include salts,sugars, and the like. In many embodiments, the agent that is employed torender the solution hypertonic is one or more, usually no more thanthree, and more usually no more than two, different salts. Generally,the salt concentration in these embodiments of the solution is at leastabout 100 mosmol, usually at least about 200 mosmol and more usually atleast about 300 mosmol, where the concentration may be as high as 3000mosmol or higher, depending on the particular salt being employed torender the solution hypertonic, where the solution may be saturated withrespect to the salt in certain embodiments. Salts that may be present inthe subject solutions include: NaCl, MgCl₂, Ringers, etc. where NaCl ispreferred in many embodiments.

[0028] Of particular interest in many embodiments is the use of ahydrogen chloride solution. In hydrogen chloride solutions that find usein the subject invention, the concentration of HCl in the solutionranges from about 0.001 to 1.0 N, usually from about 0.01 to 1.0 N andmore usually from about 0.1 to 1.0 N. In many embodiments, the hydrogenchloride solution will further include one or more salts which make thesolution hypertonic, as described above. In certain preferredembodiments, the salt is NaCl, where the concentration of NaCl in thesolution is at least 0.05 M, usually at least 0.10 M, and more usuallyat least 0.15 M, where the concentration may be as high as 0.25 M orhigher. In certain embodiments, the solution will be saturated withNaCl.

[0029] Of particular interest are aqueous hydrogen chloride solutionsthat consist of water, hydrogen chloride and NaCl. The concentration ofhydrogen chloride in these solutions of particular interest ranges fromabout 0.01 to 1.0 N, usually from about 0.05 to 0.5 N and more usuallyfrom about 0.075 to 0.25 N. The concentration of NaCl in these solutionsof particular interest ranges from about 0.05 to 0.25 M, usually fromabout 0.05 to 0.10 M.

[0030] In the subject methods, the vascular site, and specifically atleast one wall and usually all of the walls of the target vascular site,is contacted with the acidic solution for a period of time sufficientfor the progression of restenosis at the vascular site to be at leastslowed, if not substantially or completely inhibited. Contact with thevascular site may be accomplished in any convenient manner, so long asit results in the enhancement of fluid flow through the vascular site.

[0031] The manner in which contact is achieved may be static or dynamic.By static is meant that a predetermined amount of acidic solution isintroduced into the local environment of the vascular site andmaintained in the local environment of the vascular site for the entiretreatment period, without the addition of further quantities of acidicsolution. By dynamic contact is meant that the fresh acidic solution iscontacted with at least one surface of the target vascular site one ormore times, including continuously, during the treatment period.

[0032] In certain embodiments of the subject methods, at least onesurface of the target vascular site is continuously contacted or flushedwith the acidic fluid. In other words, the acidic fluid is introduced ina manner such that a continuous flow of the acidic solution into thevascular site and walls thereof is achieved. Where the target vascularsite is flushed with the dissolution fluid, it is preferred that thepressure in the local environment target vascular site, i.e. the areabounded by the vessel walls and the catheter system used to deliver thesolution, remains substantially isometric. By substantially isometric ismeant that the pressure in the local environment does not vary by asignificant amount, where the amount of variance over the treatmentperiod does not vary by more than about 50%, usually by not more thanabout 10% and more usually by not more than about 5%. In other words,the local environment remains substantially isobaric during thetreatment period. Accordingly, where fluid is dynamically contacted withthe surface of the target vascular site, fluid is also simultaneouslyremoved from the local environment comprising the target vascular site,such that the overall volume of fluid in the local environment remainssubstantially constant, where any difference in volume at any two giventimes during the treatment period does not exceed about 50%, and usuallydoes not exceed about 10%. As such, the dissolution fluid is introducedinto the local environment of the target lesion in a manner such thatthe local environment remains substantially isovolumetric.

[0033] Where the acidic solution is dynamically introduced into andaspirated from the target vascular site, the fluid is introduced in amanner such that the flow rate of the dissolution solution through thevascular site of the lesion is generally at least about 10 cc/min,usually at least about 20 cc/min and more usually at least about 60cc/min, where the flow rate may be as great as 120 cc/min or greater,but usually does not exceed about 1000 cc/minute and more usually doesnot exceed about 500 cc/minute, where by volume is meant the localenvironment of the target vascular site, as defined above. The totalamount of dissolution fluid that is passed through the local environmentof the target vascular site during the treatment period typically rangesfrom about 100 to 1000 cc, usually from about 200 to 800 cc and moreusually from about 400 to 500 cc. The solution is generally pressurizedto achieve the desired flow rate, as described supra. It is important tonote that the overall pressure in the local environment is maintained atsubstantially isometric or isobaric conditions. As such, the negativepressure at the entrance to the aspiration catheter, e.g. the openannulus at the distal end of the aspiration catheter, will be ofsufficient magnitude to provide for substantially isobaric conditions.Preferably, the overall pressure in the local environment is maintainedat a value ranging from about 0.1 to 3 psi, usually from a bout 0.5 to2.5 psi and more usually from about 1 to 2 psi.

[0034] The target vascular site is contacted, e.g. statically contactedor flushed (as described above), with the acidic treatment fluid orsolution for a period of time sufficient for the progression ofrestenosis in the target site to at least be slowed, if notsubstantially or completely inhibited. Generally, the period of timeduring which at least one surface of the target vascular site iscontacted with the acidic solution ranges from about 1 to 100 minutes,usually from about 1 to 30 minutes, where in certain embodiments contactis from about 1 to 5 minutes, in other embodiments contact is from about5 to 10 minutes and in yet other embodiments contact is from about 10 to30 minutes. Where contact is achieved by flushing the target vascularwith the acidic solution, the contact duration typically lasts for aperiod of time ranging from about 5 to 30 minutes, usually from about 10to 30 minutes and more usually from about 10 to 20 minutes.

[0035] In certain embodiments, the target site is also contacted with acytotoxic agent, where the agent may or may not be present in the acidicsolution as described above. Where the cytotoxic agent is not present inthe acidic solution, it is contacted with the target site in asequential manner, e.g., an alternating manner, such as alternatingcontact of acidic solution and a solution of the cytotoxic agent.Cytotoxic agents of interest include, but are not limited to:streptokinase, urokinase, heparin, enoxaparine, doxorubicin,progesterone, prednisolone, luprolide, abxicimab, FGF, transforminggrowth factor b, endothelial growth factor, α- and γ-interferon, HMGCoAinhibitor, antioxidants, hirudin, chemotherapeutic agents, e.g., taxoletc.

[0036] Any convenient fluid delivery device may be employed to contactthe target vascular site with the acidic treatment solution, asdescribed above. A large number of fluid delivery devices are known tothose of skill in the art, where such devices include those described inU.S. Pat. Nos. 4,445,892; 4,573,966; 4,610,662; 4,636,195, 4,655,746;4,824,436; 4,911,163; 5,059,178; 5,090,960; 5,163,905; 5,167,628;5,176,638; 5,195,955; 5,222,941; 5,342,306; 5,380,284; 5,460,610; and5,833,650; the disclosures of which are herein incorporated byreference. Of particular interest are those devices described in U.S.patent application Ser. Nos. 09/118,193; 09/195,291; 09/353,127;PCT/US99/15918; Ser. Nos. 09/382,571; and 09/384,860; the disclosures ofwhich are herein incorporated by reference. Also of interest are devicesthat provided for local delivery of agents while maintaining blood flowthrough a treatment site, such as the Dispatch™ catheter deviceobtainable from Boston Scientific.

[0037] The subject methods result in at least a slowing of, if not asubstantial or complete inhibition of, restenosis in the treated targetvascular site. By “slowing of the progression of” is meant that the rateof vessel narrowing at a treated vascular site is slower than the rateof vessel narrowing in a control site, e.g. a vascular site which is notcontacted with an acidic solution according to the subject methods. Theprogression of restenosis is considered to be at least slowed if therate of vessel narrowing is at least about 5%, usually at least about10% and more usually at least about 15% slower than vessel narrowing ina control target vascular site. In certain embodiments, the rate ofvessel narrowing in the treated vascular site is at least 50%, usuallyat least 60% and more usually at least 75% slower than the rate observedin control target vascular sites. In yet other embodiments, restenosisis substantially, if not completely inhibited in the treated targetvascular site, by which is meant that there is substantially no, if any,vessel renarrowing in the treated site, at least for a substantialperiod of time, e.g. for at least about 1 year, usually for at leastabout 2 years.

[0038] The subject methods find use in a variety of differentapplications in which it is desired to at least slow the progression of,if not substantially or completely inhibit the appearance of, restenosisor renarrowing of a vessel. As such, the subject methods find use inconjunction with a wide variety of vessel widening procedures.Representative vessel widening procedures with which the subject methodsmay be employed include: angioplasty, atherectomy, stenting, stentgrafting, and the like, wherein such procedures are described andreviewed at, among other places, the internet web site of the AmericanHeart Association.

[0039] A variety of hosts are treatable according to the subjectmethods. Generally such hosts are “mammals” or “mammalian,” where theseterms are used broadly to describe organisms which are within the classmammalia, including the orders carnivore (e.g., dogs and cats), rodentia(e.g., mice, guinea pigs, and rats), lagomorpha (e.g. rabbits) andprimates (e.g., humans, chimpanzees, and monkeys). In many embodiments,the hosts will be humans.

[0040] Kits

[0041] Also provided by the subject invention are kits for use in aleast slowing the progression of, if not substantially or completelyinhibiting the appearance of, restenosis in a target vascular site. Thesubject kits at least include: an acidic solution or precursors thereofand a fluid delivery means for delivering the acid solution to thetarget vascular site. The solution or one or more precursors thereof maybe present in a container(s), e.g. a flexible bag, a rigid bottle, etc.For kits that are to be used in methodologies in which the fluid isflushed through the local environment of the target vascular site, theamount of acidic fluid present in the kit ranges from about 0.5 to 500liters, usually from about 0.5 to 200 liters and more usually from about0.5 to 100 liters. In many of these embodiments, the amount of acidicfluid in the kit ranges from 0.5 to 5 liters, usually from about 0.5 to2.0 liters and more usually from about 0.5 to 1.5 liters. In contrast,where the fluid is to be contacted statically with the vascular site,the kit may include much less dissolution fluid. In these embodiments,the amount of dissolution fluid that may be present in the kit may rangefrom about 0.5 ml to 100 ml, usually from about 5 ml to about 50 or 20ml, and more usually from about 5 to 15 ml. As mentioned above, the kitmay alternatively include precursors of the dissolution solution for usein preparing the solution at the time of use. For example, theprecursors may be provided in dry form for mixing with a fluid, e.g.water, at the time of use. The kits also include a fluid delivery meansfor delivering the acidic fluid to the target vascular site. Generally,the kits include a catheter device or system, where representativecatheter devices and systems are described in supra. The kits mayfurther include one or more additional components and accessories foruse with the subject catheter systems, including tubing for connectingthe various catheter components with fluid reservoirs, syringes, pumpingmeans, etc., connectors, one or more guidewires, dilators, vacuumregulators, etc. Finally, the kits include instructions for practicingthe subject methods, where such instructions may be present on one ormore of the kit components, the kit packaging and/or a kit packageinsert.

[0042] The following examples are offered by way of illustration and notby way of limitation.

Experimental

[0043] I. Rabbit Assay

[0044] The following protocol was used to test various solutions fortheir effect on smooth muscle cell proliferation in arterial wallsfollowing angioplasty. A segment of the abdominal aorta of a New ZealandWhite rabbit (>4 kg) is rendered bloodless by inserting catheters bothproximally and distally to the region, inflating balloons at the distaltip of each catheter to occlude blood flow and isolating the segment,and flushing the segment with heparinized buffer. Next, a test solutionis circulated through the region (various test solutions are describedbelow), followed by flushing and deflation of the balloons.

[0045] The response of the treated segments to various test solutionsover time was characterized histologically. FIGS. 1A and 1B show anormal untreated aorta at both 25× and 100× magnification. FIG. 2A and2B show an aorta that was ballooned and treated with a control salinesolution at 2 weeks. In the figures, the superpositional zone on theleft is neointimal hyperplasia infilling the lumen. FIG. 2A is 25× andFIG. 2B is 100× magnification. FIGS. 3A and 3B show an aorta (at 25× and100× magnification, respectively) that was ballooned and then treatedwith a 1 N HCl solution adjusted with sufficient NaCl to have an osmoticpressure of 300 mosmols. FIGS. 4A and 4B (at 25× and 100× magnification,respectively) show the histology of an aorta that was ballooned and thentreated with a 0.1 N HCl solution adjusted with sufficient NaCl to havean osmotic pressure of 300 mosmols. FIGS. 5A and 5B show an aorta (at25× and 100× magnification, respectively) that was ballooned and treatedwith a control saline solution at 3 days. The absence of cell nuclei inthe medial layer indicates cell necrosis, likely due to the crushingmechanical injury during the balloon inflation.

[0046] The above results demonstrated that treatment of a balloonedaorta with an acidic solution inhibits subsequent smooth muscle growthand therefore is effective in preventing restenosis.

[0047] II. A 50 year old male having a coronary artery occlusion istreated using balloon angioplasty according to standard surgicalprotocols. Balloon angioplasty results vessel widening by compressingthe plaque initial present in the target vessel site against the wallsof the vessel. Following balloon angioplasty, the fluid delivery devicedescribed in U.S. patent application Ser. No. 09/384,680 is used toflush the treated vascular site with an acidic solution according to theprotocol provided below. An introducer sheath is placed in a suitablelocation and a guidewire is inserted and advanced to the target vascularsite. The catheter system described in U.S. patent application Ser. No.09/384,680 is employed as follows. The partial occlusion catheter deviceis inserted so that the distal end of the device is at a position suchthat the balloon at the distal end of the insert is on the far side ofthe target vascular site. A system as shown in FIG. 5B of the referencedapplication is then employed to inflate the balloon of the insert,establish a bloodless local environment and flush the target vascularsite with acidic fluid. Following treatment, the progression ofrestenosis in the treated site is at least slowed.

[0048] It is evident from the above discussion and results that improvedmethods of treating restenosis are provided. Specifically, the subjectmethods provide for a simple, safe and effective means for at leastslowing the progression of, if not preventing, restenosis. The subjectmethods are simple in that readily manufactured and safe acidicsolutions are employed. The subject methods are also safe, in thatrelatively non-toxic agents are locally administered. Despite theirsafety and simplicity, the subject methods provide an effective methodfor at least reducing the progression of restenosis. As such, thesubject invention represents a significant contribution to the field.

[0049] All publications and patent applications cited in thisspecification are herein incorporated by reference as if each individualpublication or patent application were specifically and individuallyindicated to be incorporated by reference. The citation of anypublication is for its disclosure prior to the filing date and shouldnot be construed as an admission that the present invention is notentitled to antedate such publication by virtue of prior invention.

[0050] Although the foregoing invention has been described in somedetail by way of illustration and example for purposes of clarity ofunderstanding, it is readily apparent to those of ordinary skill in theart in light of the teachings of this invention that certain changes andmodifications may be made thereto without departing from the spirit orscope of the appended claims.

What is claimed is:
 1. A kit for use in at least inhibiting theprogression of restenosis at a vascular site of a host, said kitcomprising: a solution having a subphysiologic pH; and a means fordelivering said solution to a vascular site of a host.
 2. The kitaccording to claim 1 , wherein said solution is an inorganic acidsolution.
 3. The kit according to claim 2 , wherein said inorganic acidsolution is a hydrochloric acid solution.
 4. The kit according to claim2 , wherein said inorganic acid solution further includes a salt.
 5. Thekit according to claim 4 , wherein said salt is NaCl.
 6. The kitaccording to claim 1 , wherein said means for delivering said solutionis a means for flushing said vascular site with said solution.
 7. Thekit according to claim 6 , wherein said means is a catheter.
 8. A kitfor use in at least inhibiting the progression of restenosis at avascular site of a host, said kit comprising: a solution having a pH ofless than about 4; and a means for delivering said solution to avascular site of a host.
 9. The kit according to claim 8 , wherein saidsolution is an inorganic acid solution.
 10. The kit according to claim 9, wherein said inorganic acid solution is a hydrochloric acid solution.11. The kit according to claim 9 , wherein said inorganic acid solutionfurther includes a salt.
 12. The kit according to claim 11 , whereinsaid salt is NaCl.
 13. The kit according to claim 8 , wherein said meansfor delivering said solution is a means for flushing said vascular sitewith said solution.
 14. The kit according to claim 8 , wherein saidmeans is a catheter.
 15. A kit for use in at least inhibiting theprogression of restenosis at a vascular site of a host, said kitcomprising: a solution having a pH of less than about 2; and a means fordelivering said solution to a vascular site of a host.
 16. The kitaccording to claim 15 , wherein said solution is an inorganic acidsolution.
 17. The kit according to claim 16 , wherein said inorganicacid solution is a hydrochloric acid solution.
 18. The kit according toclaim 16 , wherein said inorganic acid solution further includes a salt.19. The kit according to claim 18 , wherein said salt is NaCl.
 20. Thekit according to claim 15 , wherein said means for delivering saidsolution is a catheter means for flushing said vascular site with saidsolution.